Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse

Between history and values: A study on the nature of interpretation in international law

My thesis discusses the place of evaluative judgements in the interpretation of general international law. It concentrates on two questions. First, whether it is possible to interpret international legal practices without making an evaluative judgement about the point or value that provides the best justification of these practices. Second, whether the use of evaluative judgements in international legal interpretation threatens to undermine the objectivity of international law, the neutrality of international lawyers or the consensual and voluntary basis of the international legal system. I answer both questions in the negative. As regards the first, I argue that international legal practice has an interpretive structure, which combines appeals to the history of international practice with appeals to the principles and values that these practices are best understood as promoting. This interpretive structure is apparent not only in the claims of international lawyers about particular rules of international law (here I use the rule of estoppel as an example) but also in the most basic intuitions of international theorists about the theory and sources of general international law. I then argue that some popular concerns to the effect that the exercise of evaluation in the interpretation of international law will undermine the coherence or the usefulness of the discipline are generally unwarranted. The fact that international legal practice has an interpretive structure does not entail that propositions of international law are only subjectively true, that the interpreter enjoys license to manipulate their meaning for self-serving purposes, or that international law will collapse under the weight of irresolvable disagreements, divisions and conflicts about its proper interpretation